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Week 6 Case Presentation

Week 6 Case Presentation. Neuroendocrine Malignancy. Introduction.

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Week 6 Case Presentation

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  1. Week 6 Case Presentation • Neuroendocrine Malignancy

  2. Introduction • JR, 51 F previously working at Marketing division in Monash Uni, presented for r/v prior to her monthly Zometa (Zoledronic Acid) infusions for metastatic bronchial carcinoid tumour which was diagnosed in Mar 2010 following worsening non-productive cough and dyspnoea, and 20kg LOW. No significant past medical or family history of cancer was noted, and JR is a life-long non-smoker and has NKDA. She is currently well and ambulating, but experiences moderate fatigue limiting her ADLs (ECOG performance status 2)

  3. HOPC • Feb 2010 • Worsening non-productive cough over a few months associated with LOW of 20kg over 4 mths, worsening dyspnoea and LOA. • Nil chest pain, haemoptysis, fever / flushing, NS, chills/shakes, lumps felt, change in bowel or urinary habits • Sought medical assistance in Feb 2010 • CT scan arranged - highly vascularised lesion in the left lower lobe.

  4. PMHx • AC joint dissection in 2012 • IVF x 4C in 2004 • GORD • Sinusitis • NKDA • Nil regular meds previously

  5. FHx • No significant history of cancer in the family

  6. Social Hx • Avid cook, ensures well-balanced meals • Good social support • Nil financial issues, on private insurance

  7. Plan • Referred for bronchoscopy • Histopathology consistent with a bronchial carcinoid tumour • Urinary 5-HIAA : 110 H • HRCT scan - highly vascularised, non-spiculated mass in the left lower lobe. 4.4 x 3.2 x 5 cm. 2 small left posteroinferior • Dx: Bronchial carcinoid tumour AJCC Stage I/B (T2 N1 M0) • Referred to surgeon for VATS minimally invasive thorascopically assisted left lower lobectomy • Nuclear medicine octreotide study - Normal • Refer to Medonc for further management • commence on Somatulin (Lanreotide) 120mg

  8. F/up • Urinary 5-HIAA • 13/2/11 : 186; 11/8/11: 372H • Chromogranin A increased • 25/10/12 : 121 ; 9/5/13 : 158

  9. Mets • 18 Jun 2012 • P/W worsening (L) hip pain during routine r/v • XR showed radiolucent area in (L) acetabular region • whole body bone scan performed subsequently - mets to (L) hip • Repeat urinary 5-HIAA and chromagranin - both elevated • Plan : • RT + Commence on Zometa + continue on Somatulin

  10. Mets • 15 Feb 2013 • c/o tenderness over skull and (L) shoulder • CT brain, skull, chest - multiple liver mets • Plan • Liver Biopsy - consistent with mets from bronchial carcinoid tumour • LFTs - normal • Refer for IV radionuclide therapy @ Peter Macallum- require PET octreoscan • Mets in liver • pagetic changes detected in left clavicle and ilium

  11. Mets • FDG PET/CT & GaTate Functional Imaging performed • Ki-67 <5% • low somatostatin expression at sites of disease in abdomen and pelvis - more de-differentiated disease • ineligible for IV radionuclide therapy - recommend commencement of IV ChemoRx • Recommend cessation of Somatulin due to low somatostatin expression

  12. Chemotherapy • Commenced of 6C CBDCA / Etoposide • Experienced recurrent anaemia requiring multiple transfusions post-chemo, profound fatigue, anorexia, n/v, cancer-related pain and multiple episodes of neutropaenia requiring admissions • Developed depression - commence on mirtazapine; referral to psycho-oncologist • ChemoRx was poorly tolerated - only 5C were completed • MRI showed stable disease as of 27/8/13 • Commence of monthly Zometa (Zoledronic Acid)

  13. CEA levels

  14. Current issues • Moderate fatigue - unable to work but ADLs remain relatively good • Social isolation • Residual (L) shoulder pain - commence on Lyrica (pregabalin) • Depression - mirtazapine 60mg • Poor appetite - commence on dexamethasone 4mg for motivation / energy / appetite

  15. Current Medications • Lyrica 75mg - neuropathic pain • Magmin 500mg • Avanza 60mg - depression • Dexamethasone 4mg • Durogesic patch 25mcg/h • Endone 5mg • Seretide Accuhaler • Zometa

  16. Neuroendocrine Tumours

  17. Introduction • neoplasms that arise from the cells of the endocrine and nervous system • Classification : well-differentiated, low grade malignancy, high grade malignancy • Types • GEP-NETs - 2/3 of all GEP-NETs carcinoid, 1/3 PNET • Lung (SCLC, carcinoid, LCNEC) • Pituitary, Thymus, Parathyroid, Thyroid, EPSCC, adrenal, phaeochromocytomas, peripheral nervous system, breast, GU tract

  18. Introduction • Expresses unique syndromes & biochemical markers • Steroids - usually by adrenal cortex / gonads • Peptide hormones & catecholamines • APUD - 5HT, NA/Adr, Histamines, Kinins • Peptide hormones • GI hormones • MEN syndrome

  19. MEN Syndromes • MEN1 [TSG @ 11q13] • pituitary tumours + pancreatic islet cell tumours + parathyroid tumours • MEN 2 [ret oncogene @ 10q11] • MEN2A - medullary CA of thyroid + Bilateral phaeochromocytoma + parathyroid hyperplasia / adenoma • MEN 2B - medullary CA of thyroid + bilateral phaeochromocytoma + multiple mucosal ganglioneuromas • Cushing syndrome may develop as a consequence of ectopic ACTH production

  20. Carcinoid Tumours • <1% of all tumours • may be in association with MEN1 • Primary tumour usually an APUD - small, commonly located in the small intestine but may also be found in stomach / colorectal / lung / ovary • Mets • liver mets are common; may result in liver failure with replacement of functional liver tissue with tumour • bone mets are usually osteoblastic • desmoplastic response - mesenteric fibrosis causing bowel obstruction

  21. Carcinoid tumours • 30-50% of tumours are hormonally-active - carcinoid syndrome • Rare without liver mets [unless ovarian] • usually associated with malignancy • may exhibit niacin deficiencies, acromegaly, Cushing’s syndrome, peptic ulcerations, serum calcium abnormalities

  22. Carcinoid tumours • Symptoms • Endocrinologically inactive • Cough, haemoptysis, pulmonary infections, chest pain, pain from direct compression of the liver from mets • Endocrinologically-active • Hormonal : flushing, diarrhoea, hypotension, light-headedness, bronchospasm, HF, abdominal cramping, peripheral oedema, heart palpitations • Ex: HF, Hepatomegaly, cushing’s syndrome, acromegaly, chronic skin changes • precipitants : emotional stress, alcohol, exercise, eating, vigorous palpation of liver with mets

  23. Investigations • Bloods • 24h Urine 5-HIAA (>9mg/24h) • Chromogranin A • Imaging

  24. Anaesthesia • increased risk of flushing, bronchospasm and hypotension during surgery • minimise use of adrenergics and hypotensives [morphine, curare] • pre-op : octreotide 100mg SC tds 2/52 prior • peri-op : octreotide IV 50mcg/h prior to anaesthesia, increase if hypotensive • post-op : taper over 1/52

  25. Management • Symptomatic • Localised • Metastatic • Palliative

  26. Symptomatic Mx • Somatostatin analogs • decrease production of 5-HIAA • ameliorate symptoms in 90% of patients • tumouristatic with increase in PFS • Octreotide is able to induce an earlier reduction in IGF-1 levels and more marked reduction in GH levels cf. lanreotide • However, lanreotide dosing schedule does not require induction with daily octreotide (Short-acting) 14d prior to starting on octreotide LAR • recommend octreotide for ST pre-surgical treatment • recommend lanreotide for chronic therapy to boost compliance

  27. Symptomatic Mx • IFNα • better efficacy than somatostatin analogs • more acceptable SE profile

  28. Symptomatic Mx • Hypotension - mediated by kinins, PG, catecholamines • Avoid β-adrenergics; α-adrenergics & vasoconstrictive agents are preferred [methaoxamine / angiotensin] • +/- corticosteroids for hypotension prevention • Flushing -mediated kinins & histamines • Prochloperazine, phenoxybenazmine, prednisone, benadryl + tagament, methyldopa • Avoid MAO-I

  29. Symptom management • Bronchospasm - mediated by histamine : aminophylline • Diarrhoea - mediated by serotonin : imodium, lomotil, zofran, cyproheptadine • Bowel obstruction - NGT + IV therapy • Pellagra - daily niacin • Right Ventricular failure - avoid valve replacement. manage with diuretics, refer

  30. Localised disease • Surgery remains the mainstay of treatment for cure and increase in overall survival with debulking • Partial Hepatectomy may be performed if liver mets are confined to an area of the liver

  31. Chemotherapy • In general NETS do not show high degree of sensitivity to chemotherapy • low mitotic rates • presence of high levels of bcl-2 • increased expression of multi-drug resistance gene • Response rate <30% • Applicable situations include • aggressive disease • high proliferation rates • aggressive pancreatic NETS - chemosensitive with RR ~40-70%

  32. Metastatic Disease • Pancreatic NET • Typical : Streptozocin-based chemotherapy, Everolimus, Sunitinib • Everolimus + octreotide LAR showed a 5mth delay in tumour progression c.f. octreotide alone • Atypical - As with GI-NET

  33. Streptozocin • Single agent chemotherapy has insignificant RR <10% • STZ has shown to have a better survival outcome for unresectable pancreatic NETS • In combination with 5FU / Adriamycin, RR increased drastically • STZ + FU : RR 45% • STZ + Doxorubicin : RR 69%, PFS 20mths (vs. 6.9) , oS 2.2 yrs (vs. 1.4); more drug-related toxicitiies

  34. Metstatic Disease • GI-NET • cisplatin + etoposide • more signficant nausea, neurotoxicity and nephrotoxicity • carboplatin + etoposide • more significant haematological toxicities • used for patients with poor renal function

  35. Cisplatin + Etoposide • 67% of patients with poorly differentiated NETS achieved overall regression of the tumour • median survival of 19mths • No significant benefit seen in well-differentiated tumours • Carboplatin often substituted in place of cisplatin due to nephrotoxicity

  36. Metastatic Disease • High response rate to cisplatin + etoposide for patients with high grade NET of colon and rectum • Marginal anti-tumor activitiy and relatively severe toxicity for hepatobiliary or pancreatic poorly differentiated neuroendocrine carcinoma

  37. Metastatic Disease • IV Radionuclide therapy • Lutetium-177 Octreotate radiopeptide therapy • Patient selection • sufficient uptake of 111In-Octreotide or 68Ga-labelled somatostatin analogues • disseminated, hitopathologically proven relatively well-differentiated NET • Ki67 score <10% • unresectable disease

  38. Metastatic Disease • IV Radionuclide therapy • more effective as an early stage disease progression • chemotherapy is not a pre-requisite for radiopeptide therapy • cease LAR octreotide 6/52 prior to increase receptivity to radiopeptide therapy. short-acting octreotide may be used for symptomatic control in patients with debilitating symptoms

  39. Metastatic Disease • Hepatic artery chemoembolization

  40. Metastatic Disease • IV Radionuclide Therapy • 4 cycles with intervals of 6-8 weeks • response determined at 6/12 post-completion • metabolic response - comparative 177Lu-octreotate timor uptake on 24h scintiscancs post-therapy administration • objective response - CT/MRI studies @ 3-6mth intervals • biochemical response - serial chromograinin A titre, + urinary 5-HIAA levels • Symptomatic response • AE

  41. Palliative • Hepatic Artery embolisation • palliate endocrine symptoms / pain • regression of symptoms in 4/12 in 60% of patients • tumour shrinkage up to 80% • SE: pyrexia, nausea, LFT abnormalities • improved duration of response when used in conduction with chemotherapy

  42. Palliative • RT • carcinoids are relatively radio resistant - not a means of cure • mainly used for palliate e.g. bone mets

  43. Future • Bevacizumab • carcinoids tend to be highly vascularised • shown a rapid and sustained decrease in tumour blood flow with disease stabilisation / partial response achieved when used in conjunction with octreotide [c.f. IFNα + octreotide] • need ongoing trials prior to approval

  44. References • [1] Ducreux m, Baudin E, Schlumberger M. Treatment strategy of neuroendocrine tumours (review). Revue du Practicin. 2002 Feb 1; 52(3):290-6. • [2] Rougier P, Mitry E. Chemotherapy in the treatment of neuroendocrine malignant tumours (review). Digestion. 2000; 62 Suppl 1:73-8. • [3] Kosmidis PA. Treatment of carcinoid of the lung. Current Opinion in Oncology. 2004 Mar; 16(2):146-9. • [4] Strosberg JR, Nasir A, Hodul P, Kwols L. Biology and treatment of metastatic gastrointestinal neuroendocrine tumours. Gastrointestinal Cancer Research. 2007 Dec 14; 2(3):113-125. • [5] Basu Bristi, Sirohi Bhawna, Corrie P. Systemic therapy for neuroendocrine tumors of gastroenteropancreatic origin. Endocrine-related cancer. 2010; 17:75-90. • [6] National Cancer Institute. Treatment for advanced carcinoid tumours [Internet]. USA: Yao J; 2008 [updated 2008 Jun 24; cited 2014 Mar 4]. Available from : http://www.cancer.gov/clinicaltrials/featured/trials/swog-s0518 • [7] National Cancer Institute. MD anderson study find everolimus prolongs progression-free survival for patients with neuroendocrine tumours [Internet]. USA: NCI Cancer Center News; 2011 [updated 2011 Nov 30; cited 2014 Mar 4]. Available from : http://www.cancer.gov/newscenter/cancerresearchnews/2011/MDAndersonEverolimusStudy • [8] Demirkan BH, Eriksson b. Systemic treatment of neuroendocrine tumours with hepatic metastases (Review). Turkish Journal of Gastroenterology. 2012; 23(5) : 427-37. • [9] Razzore P, Colao A, Baldelli R, Gaia D, Marzullo P, Ferretti E et al. Comparison of six months therapy with octreotide versus lanreotide in acromegalic patients: a retrospective study. Clinical Endocrinology. 1999 Aug; 51(2):159-164. • [10] Clinical Oncological Society of Australia. Guidelines for the diagnosis and management of gastroenteropancreatic neuroendocrine tumours (GEP NETs) [Internet]. Australia: COSA; 2010 [updated Nov 2010; cited 2014 Mar 4]. Available from: http://wiki.cancer.org.au/australia/COSA:NETs_guidelines/Radionuclide_Therapy • [11] Casciato DA, Territo MC, editors. Manual of clinical oncology. 7th ed. Philadelphia, USA: Lippincott Williams & Wilkins. 2012. Chapter 15, Endocrine Neoplasm.; p. 408-414.

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